Respiratory impairment is a potentially life-threatening complication of mid-to upper cervical spinal cord injury (SCI). The majority of experimental studies addressing this problem have employed a high cervical (C2) injury model that interrupts transmission of respiratory signals between brainstem centers and spinal circuits involved in the regulation of respiratory muscle activity. One of the more prominent spinal respiratory networks is the phrenic motor system, which is comprised of neurons (phrenic motoneurons, PhMNs) that innervate the diaphragm -- the main respiratory muscle -- and spinal pre-phrenic interneurons which may regulate PhMN activity under specific physiological conditions. While C2 injuries have yielded valuable information about the potential for spontaneous recovery (neuroplasticity) and approaches to improve breathing post-injury, they do not reproduce the complex pathobiology of more frequently occurring mid-cervical SCIs. Such injuries result in damage to descending respiratory axons, as well as a focal loss of PhMNs and pre-phrenic interneurons (i.e., white and gray matter injury, respectively). As with other functions, the impact of white matter disruption on respiratory outcomes is well recognized. In contrast, the contribution of gray matter damage is poorly understood and possibly masked by the deficits attributed to axonal compromise. Therefore, a need exists to determine the impact of neuronal loss on respiratory deficits and neuroplasticity potential in order to guide the development of effective therapeutic strategies. In that regard, this proposal i based on the view that optimal spinal cord repair is not only dependent on restoring communication across the site of injury by promoting axonal growth, but also re-establishment of neural circuitry that in the intact spinal cord is vital to PhMN activity and ultimately diaphram function. The present proposal will employ a lateralized, mid-cervical contusion injury model to test the central hypothesis that PhMN and/or interneuronal loss impairs diaphragm function under specific respiratory conditions and thereby triggers neuroplastic changes to maintain adequate ventilation.
Aim I will investigate the effect of contusion on neurophysiological activity of spared PhMNs and the contribution of PhMN loss to changes in diaphragm function. Subsequent experiments will test whether discrete pharmacological lesions of central gray matter (i.e., interneuron deletion) in the absence of either white matter or motoneuron damage results in respiratory deficits similar to those seen after contusion.
Aim II will address the contribution of two forms of respiratory plasticity in spared contralateral phrenic and non-phrenic motor systems (e.g. intercostal) to breathing behavior by simultaneous monitoring of inspiratory muscle activity and ventilation in awake animals. A battery of neuroanatomical tracing approaches will be then used to define changes the underlying neural substrate that could be associated with this plasticity. These studies of an anatomically and functionally defined spinal network are likely to have significant implications leading to a more comprehensive understanding of white vs. gray matter contributions to other SCI-related functional outcomes.

Public Health Relevance

Many spinal cord injuries (SCIs) occur in the neck region (cervical spinal cord) and result in impaired breathing due to disruption of nerve cells and fibers that control activity of the diaphragm (the primary muscle of inspiration). To obtain greater definition of therapeutic opportunities requires an understanding of how tissue damage and loss contribute to deficits in breathing and what opportunities exist for promoting repair and lasting recovery. Using an animal model of cervical SCI that emulates the basic pathology and weakened breathing capacity seen in patients with similar injuries, the proposed research will address these important issues.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS054025-08
Application #
8601964
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Jakeman, Lyn B
Project Start
2006-01-01
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Florida
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Sunshine, Michael D; Ganji, Comron N; Reier, Paul J et al. (2018) Intraspinal microstimulation for respiratory muscle activation. Exp Neurol 302:93-103
Mercier, L M; Gonzalez-Rothi, E J; Streeter, K A et al. (2017) Intraspinal microstimulation and diaphragm activation after cervical spinal cord injury. J Neurophysiol 117:767-776
Nair, Jayakrishnan; Bezdudnaya, Tatiana; Zholudeva, Lyandysha V et al. (2017) Histological identification of phrenic afferent projections to the spinal cord. Respir Physiol Neurobiol 236:57-68
Sandhu, M S; Ross, H H; Lee, K Z et al. (2017) Intraspinal transplantation of subventricular zone-derived neural progenitor cells improves phrenic motor output after high cervical spinal cord injury. Exp Neurol 287:205-215
Gonzalez-Rothi, Elisa J; Streeter, Kristi A; Hanna, Marie H et al. (2017) High-frequency epidural stimulation across the respiratory cycle evokes phrenic short-term potentiation after incomplete cervical spinal cord injury. J Neurophysiol 118:2344-2357
Lee, Kun-Ze; Sandhu, Milapjit S; Dougherty, Brendan J et al. (2015) Hypoxia triggers short term potentiation of phrenic motoneuron discharge after chronic cervical spinal cord injury. Exp Neurol 263:314-24
Sandhu, M S; Baekey, D M; Maling, N G et al. (2015) Midcervical neuronal discharge patterns during and following hypoxia. J Neurophysiol 113:2091-101
Gonzalez-Rothi, Elisa Janine; Rombola, Angela M; Rousseau, Celeste A et al. (2015) Spinal interneurons and forelimb plasticity after incomplete cervical spinal cord injury in adult rats. J Neurotrauma 32:893-907
Gonzalez-Rothi, Elisa J; Lee, Kun-Ze; Dale, Erica A et al. (2015) Intermittent hypoxia and neurorehabilitation. J Appl Physiol (1985) 119:1455-65
Kwon, Brian K; Soril, Lesley J J; Bacon, Mark et al. (2013) Demonstrating efficacy in preclinical studies of cellular therapies for spinal cord injury - how much is enough? Exp Neurol 248:30-44

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